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R C Donehower

Publications and source records attributed to R C Donehower.

At least 73 records · Page 4Linked to original sources
PubMed1994

Clinical pharmacology and metabolism of Taxol (paclitaxel): update 1993.

Paclitaxel may be one of the most important anticancer agents to be developed over the past 2 decades. With its unique mechanism of action as an inducer of tubulin assembly, paclitaxel has demonstrated impressive antitumor activity in patients with breast, lung (both non-small cell and small cell), head and neck, and advanced and platinum-refractory ovarian carcinomas. Unfortunately, there has been a relative lack of pharmacologic data available for paclitaxel, compared with other agents in similar phases of development. This scarcity of data is due, in part, to the aqueous insolubility of paclitaxel and to difficulties in developing sensitive analytic assays to measure the full range of drug concentrations achieved in small animals, both of which have limited preclinical pharmacologic studies. This report reviews the pharmacology of paclitaxel as ascertained during early clinical trials. Although most early studies used prolonged intravenous administration schedules of the agent as both monotherapy and in chemotherapy combinations, more recent studies have evaluated shorter administration schedules. In addition, available information pertaining to the pharmacodynamic and metabolic profiles of paclitaxel are discussed. Such information may be useful in designing rational treatment regimens of paclitaxel as a single agent and in chemotherapy combinations, potentially resulting in the optimal utilization of this important agent in cancer chemotherapeutics.

Animals↗
PubMed1993

Phase I and pharmacological study of the pulmonary cytotoxin 4-ipomeanol on a single dose schedule in lung cancer patients: hepatotoxicity is dose limiting in humans.

4-Ipomeanol (IPO), a naturally occurring pulmonary toxin, is the first cytotoxic agent to undergo clinical development based on a biochemical-biological rationale as an antineoplastic agent targeted specifically against lung cancer. This rationale is based on preclinical observations that metabolic activation and intracellular binding of IPO, as well as cytotoxicity, occurred selectively in tissues and cancers derived from tissues that are rich in specific P450 mixed function oxidase enzymes. Although tissues capable of activating IPO to cytotoxic intermediates in vitro include liver, lung, and kidney, IPO has been demonstrated in rodents and dogs to undergo in situ activation, bind covalently, and induce cytotoxicity preferentially in lung tissue at doses not similarly affecting liver or kidneys. Although the drug was devoid of antitumor activity in the conventional murine preclinical screening models, cytotoxic activity was observed in human lung cancers in vitro and in human lung cancer xenografts in vivo, adding to the rationale for clinical development. Somewhat unexpectantly, hepatocellular toxicity was the dose-limiting principal toxicity of IPO administered as a 30-min infusion every 3 weeks to patients with lung cancer. In this study, 55 patients received 254 courses at doses almost spanning 3 orders of magnitude, 6.5 to 1612 mg/m2. Transient and isolated elevations in hepatocellular enzymes, predominantly alanine aminotransferase, occurred in the majority of courses of IPO at 1032 mg/m2, which is the recommended IPO dose for subsequent phase II trials. At higher doses, hepatocellular toxicity was more severe and was often associated with right upper quadrant pain and severe malaise. Toxic effects were also noted in other tissues capable of activating IPO, including possible nephrotoxicity in a patient treated with one course of IPO at 154 mg/m2 and severe, reversible pulmonary toxicity in another patient who received nine courses of IPO at doses ranging from 202 to 826 mg/m2. Although individual plasma drug disposition curves were well described by a two-compartment first order elimination model, The relationship between IPO dose and area under the disposition curve was curvilinear, suggesting saturable elimination kinetics. At the maximum tolerated dose, the mean half-lives (lambda 1 and lambda 2) were 6.7 and 114.5 min, respectively. Renal excretion of parent compound accounted for less than 2% of the administered dose of IPO. An unidentified metabolite was detected in the plasma of patients treated at higher doses. No objective antitumor responses were observed; however, stable disease persisted for at least eight courses in 27% of patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1993

The current status of camptothecin analogues as antitumor agents.

The nuclear enzyme topoisomerase I (topo I) has been recently recognized as the target for the anticancer drug camptothecin (CPT) and its derivatives. Two of the agents that target this enzyme--topotecan (TPT) and CPT-11--appear to be active against a broad range of human tumors. In the following presentation, we review 1) the role of topo I in normal cells, 2) the chemistry and proposed mechanism of action of CPT and its analogues, 3) the results of preclinical and clinical testing of TPT and CPT-11, and 4) mechanisms of resistance to these agents. In normal cells, topo I is thought to be involved in gene transcription and DNA replication. During the course of its normal catalytic cycle, topo I transiently forms a covalent bond with DNA. CPT and its derivatives slow the religation step of the enzyme and stabilize the covalent adduct between topo I and DNA. In S-phase cells, advancing replication forks convert these topo I-DNA adducts into double-strand breaks that appear to be responsible for the cytotoxicity of these agents. Preclinical studies demonstrate antineoplastic activity for TPT and CPT-11 in a variety of tumor models. Phase I studies have identified neutropenia as the dose-limiting toxicity for both drugs. Gastrointestinal effects might also be dose-limiting for CPT-11 administered on some schedules. CPT-11 has shown antitumor activity in phase II trials for patients with carcinomas of lung, cervix, ovary, colon, and rectum and for patients with non-Hodgkin's lymphoma. Phase II studies of TPT are in progress. Resistance to the cytotoxic effects of these agents might result from decreased production of topo I or from production of a mutated form of topo I. In addition, decreased metabolic activation of CPT-11 (which is a pro-drug) and active efflux of TPT by P-glycoprotein-mediated transport might contribute to resistance. As agents with a novel mechanism of action, tolerable toxicity, and encouraging antitumor activity in early clinical trials, TPT and CPT-11 are undergoing further clinical development. If these agents can be successfully combined with other active chemotherapy agents, the topo I-directed agents offer the potential for significant advances in the treatment of patients with a variety of malignancies.

Animals↗
PubMed1993

Sequence-dependent cytotoxic effects due to combinations of cisplatin and the antimicrotubule agents taxol and vincristine.

The antineoplastic activity that taxol has demonstrated in advanced ovarian cancer and other neoplasms in which the platinum analogues are among the most active agents has been the impetus for the development of taxol/platinum combination regimens. Since both classes of agents are known to induce cell-cycle-dependent effects and to delay cell-cycle traverse in specific phases of the cycle, an evaluation of drug sequence dependence was incorporated into initial clinical studies of the drug combination. To complement clinical studies, sequence-dependent interactions were assessed in vitro using L1210 leukemia. Cytotoxicity resulting from the combination of taxol and cisplatin was significantly increased over that achieved with cisplatin alone only when cisplatin was administered after taxol. This sequence was significantly superior to both the reverse sequence and to simultaneous drug treatment. Results achieved with sequence iterations of vincristine and cisplatin were nearly identical. In addition, alkaline-elution studies, using the optimal sequence of cisplatin and either taxol or vincristine, demonstrated that these antimicrotubule agents do not increase the formation of cisplatin-induced DNA interstrand and DNA-protein crosslinking over that produced by cisplatin alone. Although the mechanisms for the sequence-dependent cytotoxic interactions between cisplatin and the antimicrotubule agents have not been determined, it is likely that antagonistic interactions occur with the suboptimal sequences, probably because of cell-cycle-dependent phenomena.

Animals↗
PubMed1993

An overview of experience with TAXOL (paclitaxel) in the U.S.A.

TAXOL (paclitaxel) is a unique new antineoplastic agent that has generated a considerable amount of scientific interest from many disciplines since it entered clinical trials in the early 1980s. There are a number of reasons for this interest. The natural biological source for this agent is the bark of the Pacific yew in the ancient forests of the northwestern U.S.A. The initial problems with supply of the agent and the desirability of a renewable source has stimulated the creativity of medicinal chemists and others interested in alternate sources of supply. The unique mechanism of action and the effect of TAXOL on microtubule structure and function continues to be the subject of intense investigative interest. Clinical investigators have had to contend with troublesome and potentially serious toxicities, which have threatened the development of TAXOL, but have been rewarded with a drug that appears to have broad antitumor activity against a number of advanced solid tumors in man. The purpose of this review is to provide an overview of the clinical experience with TAXOL, which has been developed in the U.S.A. over the last 10 years with more than 4,000 patients, and to outline what issues remain in the optimization of its use.

Breast Neoplasms↗
PubMed1993

Phase I and pharmacologic study of paclitaxel and cisplatin with granulocyte colony-stimulating factor: neuromuscular toxicity is dose-limiting.

PURPOSE: To determine the maximum-tolerated doses (MTD), the principal toxicities, and the pharmacologic behavior of high doses of Taxol (paclitaxel; Bristol-Myers Squibb, New York, NY) combined with cisplatin and granulocyte colony-stimulating factor (G-CSF). PATIENTS AND METHODS: Untreated and minimally pretreated solid-tumor patients received 24-hour infusions of Taxol on day 1 followed by cisplatin on day 2 and G-CSF, 5 micrograms/kg/d subcutaneously (SC), beginning on day 3. Treatment was repeated every 3 weeks. Starting doses of Taxol and cisplatin were 135 and 75 mg/m2, respectively. RESULTS: The development of a severe peripheral neuropathy and/or severe myalgias precluded the chronic administration of Taxol and cisplatin with G-CSF at doses greater than 250 mg/m2 and 75 mg/m2, respectively. At this dose, the mean Taxol steady-state plasma concentration (Css) exceeds concentrations capable of inducing pertinent antimicrotubule effects in vitro. The severity of the neuropathy was related to the cumulative dose of Taxol, the magnitude of the dose administered during each treatment, and the presence of a pre-existing medical disorder associated with peripheral neuropathy. A proximal myopathy of modest severity also was documented. Although severe neutropenia occurred frequently, especially at the MTD, it was rarely associated with fever (8% of courses), and absolute neutrophil counts (ANCs) less than 500/microL never persisted for more than 5 days. Responses were noted in non-small-cell lung cancer (NSCLC) and head and neck, breast, and esophageal cancers. CONCLUSION: Taxol and cisplatin doses of 250 mg/m2 and 75 mg/m2, respectively, can be administered repetitively with G-CSF to untreated and minimally pretreated patients. However, these doses are not recommended for patients with pre-existing neuropathies until additional experience in high-risk patients is obtained. Although this Taxol dose is nearly 85% higher than the dose that can be combined with cisplatin in the absence of G-CSF, this high-dose regimen should not be used outside the investigational setting until a dose-response relationship has been demonstrated for Taxol in randomized clinical trials.

Adult↗
PubMed1993

Successful re-treatment with taxol after major hypersensitivity reactions.

PURPOSE: To describe the successful re-treatment of eight patients who had major hypersensitivity reactions (HSRs) to taxol and to suggest a regimen for re-treating patients who develop major HSRs. PATIENTS AND METHODS: The treatment courses of eight patients who developed major HSRs and were rechallenged with taxol were reviewed. Patients in this report represent all patients who are known to have been rechallenged with taxol after major HSRs. RESULTS: The most common approach used to rechallenge patients consisted of premedication with multiple high doses of corticosteroids and H1- and H2-histamine antagonists followed by the initiation of the taxol infusion at a reduced rate. All patients who experienced major HSRs were rechallenged successfully. After the rechallenge, these patients received 32 additional courses of taxol without HSRs. CONCLUSION: Re-treatment with taxol after major HSRs is feasible using multiple high doses of corticosteroids and antihistamine premedications and a reduced taxol infusion rate under close supervision. This approach may represent a valid alternative to the termination of taxol; however, a prospective evaluation is required to determine the true efficacy of this approach.

Aged↗
PubMed1993

Neurotoxicity of Taxol.

Neurotoxicity, manifested primarily by a motor and sensory polyneuropathy, is the principal nonhematological side effect of Taxol. Available evidence suggests that Taxol produces a toxic effect involving either axons or ganglion cell bodies, or both, rather than a myelinopathy. As with other toxic polyneuropathies, patients with preexisting peripheral neuropathies, such as those caused by diabetes mellitus or ethanol, appear to be particularly predisposed to developing neurological toxicity. The incidence and severity of the neuropathic manifestations also appear to be related to the Taxol dose level, the cumulative dose of Taxol, and possibly to the use of Taxol in combination with cisplatin. Rarely, manifestations of autonomic and central nervous system dysfunction occur. Taxol also induces myalgias in the peri-treatment period, especially when used in high doses, and a myopathy has been noted in patients treated with high doses of Taxol administered alone and in combination with cisplatin. Although dose-response relationships for Taxol have not been clearly established, these neuromuscular effects are likely to become a significant clinical problem if higher doses of Taxol are used with hematopoietic colony-stimulating factors. The neuromuscular effects of Taxol, including symptoms, physical and electrophysiological manifestations, and predisposing factors, as well as agents that may be used for neuroprotection, are discussed in this report.

Humans↗
PubMed1993

Hepatic metabolism and biliary excretion of Taxol in rats and humans.

To date there have been limited studies of the metabolism and disposition of Taxol in animals and humans. Renal disposition of unmetabolized Taxol has been documented to account for a maximum of 5% to 10% of an administered dose of Taxol in humans, but the principal processes involved in drug disposition, particularly the roles of biliary excretion and drug metabolism, have not been evaluated. Therefore, the biliary excretion of Taxol has been studied in rats and in a human patient receiving Taxol in a phase I trial. Of the total doses administered to rats and the patient, 40% and 20%, respectively, were excreted in the bile in the forms of unmetabolized Taxol and Taxol metabolites until 24 hours posttreatment. Although the biliary excretion of unmetabolized Taxol accounted for 10% and 3% of total drug disposition in the rats and in the patient, respectively, the remaining portion consisted of several metabolites. Nine metabolites were detected in rat bile, and five metabolites were detected in human bile. The chemical structures of four of the rat metabolites and three of the human metabolites have been identified thus far. With the exception of baccatin III, a minor metabolite found only in rat bile that lacks the side chain at C-13 position of the taxane ring, the other metabolites were monohydroxylated or dihydroxylated and had intact taxane rings and side chains at taxane ring positions C-2 and C-13. The taxane ring and both the C-2 and C-13 side chains were susceptible to hydroxylation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Clinical toxicities encountered with paclitaxel (Taxol).

Although paclitaxel (TAXOL) appears to be one of the most promising antineoplastic agents of the last decade, with demonstrated activity in advanced and refractory ovarian, breast, lung, and head and neck cancers, most clinical oncologists have had little experience with the agent. This is largely the result of the initially limited supply of paclitaxel and other obstacles encountered during early clinical development that restricted the drug's availability to a few investigational centers. Although a high incidence of major hypersensitivity reactions due to the Cremophor EL vehicle used in formulation disrupted and almost terminated the clinical development of paclitaxel, hypersensitivity reactions are no longer a serious problem consequent to the advent of effective premedication regimens and longer administration schemes. Instead, neutropenia is the principal toxicity of paclitaxel. At clinically relevant doses, absolute neutrophil count nadirs are severely depressed in most patients. The duration of severe neutropenia, however, is usually brief; treatment delays for unresolved hematologic toxicity are rare, and absolute neutrophil count nadirs are constant with repetitive dosing, suggesting that neutropenia is not cumulative. Asymptomatic sinus bradycardia has occurred in up to 29% of patients in phase II trials, and other cardiac disturbances, including atrioventricular conduction and bundle branch blocks, ventricular tachycardia, and possible ischemic manifestations, have been reported in approximately 3% of patients. Cardiac disturbances have primarily been noted in studies that used cardiac monitoring to more effectively detect and manage major hypersensitivity reactions. Although sinus bradycardia and conduction blocks appear to represent true toxicities, ventricular tachycardia and ischemic manifestations, which have largely been observed in patients with preexisting cardiac disease, may not be due to paclitaxel. In view of the lack of clinical significance of the cardiac effects and their infrequent occurrence, cardiac monitoring during paclitaxel is not recommended for patients without cardiac risk factors. However, until precise risk factors can be defined, patients with a significant antecedent cardiac history are generally not considered to be good candidates for paclitaxel therapy. Neurotoxicity, characterized principally by peripheral neurosensory manifestations, has generally been of mild to moderate severity, even in heavily pretreated patients at paclitaxel doses < or = 200 mg/m2. However, some patients have developed a severe sensory-motor polyneuropathy at higher doses of paclitaxel (given as a single agent or in combination with cisplatin). Patients with an antecedent peripheral neuropathy or coexisting medical illnesses associated with peripheral neuropathy (such as diabetes mellitus and substantial prior alcohol use) appear to be especially prone to developing peripheral neuropathy.(ABSTRACT TRUNCATED AT 400 WORDS)

Alopecia↗
PubMed1993

The clinical pharmacology of paclitaxel (Taxol).

Although paclitaxel (TAXOL) may be one of the most important antineoplastic agents to emerge from drug screening over the last several decades, with activity demonstrated to date against ovarian, breast, lung, and head and neck cancers, there is a relative lack of pharmacologic data available compared with other agents in similar phases of development. This has been due to the aqueous insolubility of paclitaxel and the inherent insensitivity of standard analytic assays in measuring the full range of biologically significant drug concentrations achieved in small animals, a fact that has limited preclinical pharmacologic studies. This report reviews the clinical pharmacology of paclitaxel as determined during early single-agent studies with the drug administered in various intravenous and intraperitoneal schedules and in combination with other antineoplastic agents. Additionally, available information pertaining to the pharmacodynamic and metabolic profiles of paclitaxel is discussed. Such information may be useful in designing rational treatment regimens using paclitaxel as a single agent and in chemotherapy combinations, potentially resulting in the optimal use of this important agent in cancer chemotherapeutics.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Effect of P-glycoprotein expression on the accumulation and cytotoxicity of topotecan (SK&F 104864), a new camptothecin analogue.

Topotecan (TPT, 9-dimethylaminomethyl-10-hydroxycamptothecin) is the first topoisomerase I-directed cytotoxic agent to enter clinical trials in the United States in two decades. The effect of P-glycoprotein (Pgp) overexpression on TPT cytotoxicity was examined in CHRC5 (colchicine-resistant) and AuxB1 (parental) Chinese hamster ovary cells. Examination of the IC50 values observed in colony-forming assays revealed that the CHRC5 cells were 15-fold (SD, +/- 3; n = 3) resistant to TPT after a 1-h exposure and 3.2-fold (SD, +/- 1.4; n = 4) resistant in continuous exposure experiments. Band depletion immunoblotting revealed that 4-fold higher concentrations of extracellular TPT were required to induce the formation of topo I-DNA complexes in CHRC5 cells as compared to AuxB1 cells. To assess the role of Pgp in this resistance, drug accumulation and cytotoxicity assays were repeated in the absence and presence of quinidine. Addition of quinidine enhanced TPT accumulation (measured by high-performance liquid chromatography) and diminished the IC50 for TPT to a greater extent in CHRC5 cells than in AuxB1 cells. To examine whether similar effects could be detected in Pgp-expressing human cells, MCF-7/Adriar breast cancer cells and KG1a human acute myelogenous leukemia cells were examined. Quinidine or verapamil enhanced TPT accumulation in both of these cell lines but had no effect in parental MCF-7 cells or a variety of human leukemia cell lines that do not overexpress Pgp. Cytotoxicity measurements performed by counting the number of surviving cells (MCF-7/Adriar) or employing a modified, highly stable tetrazolium dye reduction assay (leukemia cell lines) revealed that quinidine diminished the IC50 for TPT in the Pgp-overexpressing cell lines but not in the control lines. These results suggest that Pgp overexpression diminishes TPT accumulation and TPT cytotoxicity in hamster and human cells. It should be stressed, however, that these effects were substantially smaller than the effects of Pgp overexpression on the accumulation and cytotoxicity of the anthracycline daunorubicin and the epipodophyllotoxin etoposide in the same cell lines.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Hexamethylene bisacetamide in myelodysplastic syndrome: effect of five-day exposure to maximal therapeutic concentrations.

The efficacy of hexamethylene bisacetamide (HMBA), a potent polar-planar solvent which is capable of differentiating leukemias and solid tumors in vitro at clinically achievable concentrations, was studied in 16 patients with severe myelodysplastic syndromes (MDS). An adaptive control dosing algorithm was used to maintain HMBA steady-state concentrations (Css) within a narrow therapeutic window (1-2 mM) for five days every four weeks. Despite achieving the target HMBA Css during at least two courses in each of 15 patients, HMBA did not produce clinically relevant improvements in blood cell counts nor in other functional indices. Instead, HMBA induced cytopenias in the majority of these patients, most of whom had preexisting cytopenias and limited hematopoietic reserves. These disappointing results correlated with concurrent in vitro bone marrow studies from these patients in which both the HMBA concentrations that were optimal for differentiation in vitro (2-5 mM) and the HMBA Css that were achieved in this study (1-2 mM) substantially inhibited the growth of granulocyte-macrophage colony-forming units and erythroid burst-forming units. Although the mechanism responsible for the anti-proliferative effects of HMBA on hematopoietic progenitors (cytotoxicity versus terminal differentiation) could not be determined, the induction of cytopenias and lack of significant clinical improvements suggest that HMBA is cytotoxic and will not be useful alone as a differentiating agent on this schedule of administration in the treatment of MDS.

Acetamides↗
PubMed1992

An overview of the clinical experience with hydroxyurea.

In the more than 30 years since hydroxyurea was first evaluated clinically, a number of diverse and unique applications have been identified for its use. Some of these applications were apparent to investigators almost from the beginning, while others are still evolving 3 decades later as a result of ongoing research. An overview of clinical experience with hydroxyurea provides an historical perspective on a period encompassing virtually the entire era in which anticancer chemotherapy has been a recognized discipline. The critical role of the ribonucleotide reductase reaction in the regulation of DNA synthesis makes this enzyme a particularly important target site for antineoplastic therapy. The sustained interest in hydroxyurea, however, has been the result of careful clinical observations as well as basic laboratory studies, which support current attempts to identify additional uses for the drug. This overview describes the clinical development of hydroxyurea, discusses current indications, and briefly describes areas of ongoing research that may expand the clinical indications for hydroxyurea.

Humans↗
PubMed1991

Phase I and pharmacokinetic study of hepsulfam (NSC 329680).

Hepsulfam (NSC 329680), a bifunctional alkylating agent structurally related to busulfan, has entered clinical trial based on its broader preclinical antitumor activity compared with that of busulfan and its i.v. formulation which may circumvent the many problems arising from the p.o. administration of busulfan, such as significant individual differences in bioavailability. In this Phase I study, 53 patients received 95 courses of hepsulfam at doses ranging from 30 to 480 mg/m2 administered i.v. over 30 min every 28 days. Hematological toxicity was dose limiting. Leukopenia and thrombocytopenia were dose related, delayed in onset, and sustained for long durations. Toxicity was cumulative in most patients receiving more than one course. This pattern of myelosuppression suggests that hepsulfam is cytotoxic to hematopoietic stem cells. Although hematological toxicity was not particularly severe during most courses, its lengthly duration precluded the prompt administration of subsequent courses. Minimal nonhematological effects were observed. Pharmacokinetic studies revealed that the clearance rate of hepsulfam is linear over the dose range studied and that its plasma disposition is biphasic with mean alpha and beta half-lives of 19 +/- 18 (SE) min and 337 +/- 248 (SE) min, respectively. The area under the plasma clearance curve correlated with the percentage of change in WBC using a sigmoidal Emax model and with the duration of thrombocytopenia in patients with hematological toxicity. Based on the protracted duration of the toxicity of multiple doses that were greater than 210 mg/m2, the recommended starting dose for Phase II trials is 210 mg/m2. However, these trials should be pursued with caution because of the protracted nature of hepsulfam's myelosuppression. Because hepsulfam produced minimal nonhematological toxicity, substantial dose escalation above 480 mg/m2 may be possible with hematopoietic stem cell support.

Adult↗